TMEM120A/TACAN inhibits mechanically activated PIEZO2 channels

Abstract

PIEZO2 channels mediate rapidly adapting mechanically activated currents in peripheral sensory neurons of the dorsal root ganglia (DRG), and they are indispensable for light touch and proprioception. Relatively little is known about what other proteins regulate PIEZO2 activity in a cellular context. TMEM120A (TACAN) was proposed to act as a high threshold mechanically activated ion channel in nociceptive DRG neurons. Here, we find that Tmem120a coexpression decreased the amplitudes of mechanically activated PIEZO2 currents and increased their threshold of activation. TMEM120A did not inhibit mechanically activated PIEZO1 and TREK1 channels and TMEM120A alone did not result in the appearance of mechanically activated currents above background. Tmem120a and Piezo2 expression in mouse DRG neurons overlapped, and siRNA-mediated knockdown of Tmem120a increased the amplitudes of rapidly adapting mechanically activated currents and decreased their thresholds to mechanical activation. Our data identify TMEM120A as a negative modulator of PIEZO2 channel activity, and do not support TMEM120A being a mechanically activated ion channel.

Delayed Onset Muscle Soreness and Critical Neural Microdamage-Derived Neuroinflammation

“…As a result of the primary noncontact microdamage, a secondary injury phase could succeed in the form of harsher tissue damage [ 8 , 53 ]. This more pervasive tissue damage in DOMS is due to the primary impairment of proprioceptive protection, as we could experience in other noncontact injuries [ 8 , 31 , 53 , 57 , 85 ]. The pivotal involvement of other sensory neurons, such as nociceptive neurons [ 24 ], and other ion channels, e.g., TRPV1 and TRPV4 [ 25 ], could occur in this stage of the noncontact pathophysiology of DOMS [ 8 ].…”

“…Since the critical gateway to pathophysiology is proposed to be initiated at neural loci, neural interpretation and tracing of the pathophysiology from the neuronal angle could serve us with a better clinical understanding in the future. Notably, this type of somatosensory terminal impairment caused by damaging eccentric contractions is proposed to be analogous to the so-called TAD, often seen in platinum-analogue and paclitaxel chemotherapy [ 8 , 57 ]. These TAD lesions do not result in classical Wallerian-type neuronal degeneration [ 8 , 16 , 19 ].…”

“…Second, glutamate signaling is switched from vesicular-based to activated NMDA receptor-based signaling, which could be the equivalent of the aforementioned switch from monosynaptic Type Ia static firing to polysynaptic Type II static firing. Third, the lost VGLUT1 sensory encoding and the activated NMDA receptors could induce NaPICs or, even more likely, NMDA PICs [ 72 ] on motoneurons, leading to exaggerated contractions and reduced range of motion, as was suggested by Sonkodi [ 57 ], demonstrated by Del Rosario et al [ 57 ] and could be observed after nerve crush injury [ 73 , 74 ].…”

“…The accumulation of these radicals could enhance nociception and instigate distal degeneration of nerve fibers [ 16 ]. The noncontact acute proprioceptive compression axonopathy theory of DOMS implied already that ASR-derived autologous superposition of compression forces could possibly cause such a severe mechano-energetic insult on axonal mitochondrial trafficking to the proprioceptive terminals of the muscle spindles that microdamages the axon’s energy supply [ 57 ], which is akin to the aforementioned TAD-like lesion [ 16 ].…”

Miswired Proprioception in Amyotrophic Lateral Sclerosis in Relation to Pain Sensation (and in Delayed Onset Muscle Soreness)—Is Piezo2 Channelopathy a Principal Transcription Activator in Proprioceptive Terminals Besides Being the Potential Primary Damage?

“…Hence, microdamaged Piezo2 can not only become leaky to subthreshold imbalanced Ca 2+ currents in the hyperexcited and supposedly inactivated state, but also to glutamate [ 4 , 8 ]. The analogy could come from the so-called terminal arbor degeneration (TAD)-like somatosensory terminal impairment that can be often seen in platinum analogue and paclitaxel chemotherapy [ 12 , 37 ]. It is noteworthy that these TAD-like lesions do not come with classic Wallerian-type axonal degeneration and evolve through a dose limiting manner [ 12 , 13 , 14 ].…”